Genetic mouse models based on genetic susceptibility are still in their infancy. Studying the roles of susceptibility genes in cognitive processing, neuronal function, and signal transduction in the brain during development, as well as their interactions with environmental factors, will most likely give better understanding of the molecular mechanisms of the pathophysiology of schizophrenia, reveal the molecular basis of normal cognitive function and human brain development, and guide us to novel antipsychotic therapies. In this study, we review the hypothesis-based genetic mouse models of schizophrenia, highlight the susceptibility gene-based models, and discuss new strategies for genetic mouse models for schizophrenia. [unreadable] [unreadable] Whether the genetic mouse model is based on abnormal neurodevelopment, neurodevelomental candidate gene, hypodopaminergic and glutaminergic hypotheses it is very difficult to mimic symptoms of schizophrenia. Traits, or phenotypes like hyperactivity, cognitive dysfunction, abnormal social behaviors are not unique to schizophrenia and the number of individuals with that specific genotype who express that particular phenotype varies among individuals. This stresses the importance of using susceptibility genes to link the trait or behavior to schizophrenia and expect variation sin phenotypes of different genetic animal models. [unreadable] [unreadable] Schizophrenia is a polygenic disease with complex gene-gene and gene-environment interactions and genetic mouse models with single gene mutations do not address the interactions among susceptibility genes. Genetic abnormalities related to schizophrenia appear to focus on abnormalities of gene processing and regulation. New models with mutations in regulatory regions in genes will be needed to model these more complex molecular processes implicated in schizophrenia. In addition, multiple susceptibility gene defects within the same animal are needed to study gene-gene interactions in exploring the molecular mechanisms underlying the pathophysiology of this very complex, polygenic disease.[unreadable] [unreadable] In our study of catechol-o-methyltransferase (COMT), our group examined enzyme activity and protein expression in prefrontal cortex (PFC) in 6 age groups of normal controls from neonates to the aged. We found a significant increase in COMT enzyme activity from neonate to adulthood and this is paralleled by increases in protein expression. Additionally, COMT protein expression is related to the Val158Met genotype. These increases may reflect changes in the PFC dopamine system and stresses the increasing importance of COMT for PFC dopamine regulation during maturation. The increasing body of evidence which shows the COMT Val/Met polymorphism impact on prefrontal PF cognition, raises the possibility of a novel pharmacological approach for the treatment of PF lobe executive dysfunction. Efforts to enhance prefrontal-related cognition using catecholaminergic stimulant drugs, have been unsatisfactory. In another study, a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT genotype was performed. Our group measured COMT enzyme activity in peripheral blood and found significant drug effects on measures of executive function and verbal episodic memory and a significant drug effect by genotype interaction, such that COMT Val/Val improved, whereas Met/Met worsened on Tolcapone. Functional magnetic resonance imaging (fMRI) revealed a significant tolcapone-induced improvement in the efficiency of information processing in PFC during a working memory test. This study demonstrates enhancement of PF cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of dopamine signaling in the PFC.[unreadable] [unreadable] NRG1 is essential for the development and function of multiple organ systems and its dysregulation has been linked to diseases such as cancer and schizophrenia. Many human genes are known to produce more than one protein isoform through the use of alternative molecular events that determine the efficient and accurate initiation of gene transcription. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizo-related genetic variants. This study isolated and characterized full-length NRG1 type IV DNAs from the adult and fetal human brain and identified novel splice variants of NRG1. NRG1 type IV and a putative type IV protein isoform were found to be brain-specific and abundantly expressed in the fetal brain. In addition 2 novel type IV variants were identified. Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed, is processed during early development and is translated while its expression is regulated by a mutation in a regulatory element associated with risk for schizophrenia.